Neurofibromatosis 1 (NF1) is an autosomal dominant disorder resulting from a spontaneous or inherited loss-of-function mutation in the gene encoding the regulatory protein, neurofibromin (NF). NF1 is characterized by tumors (neurofibromas) associated with the peripheral nervous system and by cognitive impairments including attention deficit hyperactivity disorder and learning and memory deficits. Although the genetic basis for NF1 has been established, the biological mechanisms by which loss of one copy of NF leads to the characteristic symptoms of the disease are not well understood. Studies with transgenic mice indicate that cognitive deficits are associated with the loss of GTPase activating protein (GAP) activity of NF. This research program will focus on the cellular and molecular mechanisms by which loss of NF GAP activity can lead to cognitive dysfunction and will test the hypothesis that the normal function of NF is to maintain low basal activity in the brain-derived neurotrophic factor (BDNF) signaling pathway by deactivating the G-protein, Ras. A prediction of this hypothesis is that partial loss of NF GAP activity in NF1 creates an abnormally high basal activity in the BDNF signaling pathway, leading to the dysregulation of BDNFmediated physiological functions underlying normal leaming and memory. This will be tested by examining BDNF signaling in genetically-modified neurons lacking NF. Although BDNF, via its cognate receptor, trkB, is known to activate multiple downstream pathways, not all of these should be affected by the loss of NF. Immunoprecipitation and proteomic analysis will be used to identify and characterize functional signaling complexes containing NF and trkB. If this hypothesis withstands the critical tests outlined in this proposal, the BDNF/trkB signaling pathway will emerge as a potential target for pharmacological or other therapies that could selectively treat the cognitive symptoms of NF1; the neurofibromas may be more effectively treated with a separate therapeutic strategy. In addition to testing this hypothesis, elucidation the components of the NF signaling complex will provide new insight into the normal function of NF and may provide additional clues to potential molecular targets for the treatment of NF1.